Take references from modeling paper

Zero Order Model. The zero order model assumes that the drug dosage form does not
disaggregate and that the release of the drug is very slow, i.e. the amount of drug dissolved per
unit time is a constant value. If the function Q(t)is assumed to represent the amount of the drug
that is in solution at any time t then according to the zero order assumptions the behavior of the
drug in solution is represented by:
dQ(t)
=K 0 ( SEQ Equation¿ ARABIC33)
dt
Where K0 is a zero-order release constant which has units of concentration per unit time.
Applying definite integration (integration by parts) with respect to time over the interval [0,t].

Qt t

∫ dQ(t)=∫ K 0 dt ( SEQ Equation ¿ ARABIC34 )

Q0 0

Where Qt is the amount of drug released at time t. Q0 is the initial amount of the drug in
solution and is usually very small or assumed to be zero.

Q t −Q 0=K 0 ( t−0 ) ( SEQ Equation¿ ARABIC35)

Q t =Q0 + K 0 t (SEQ Equation¿ ARABIC36)

In order to re-define the model in terms of the variables used in this research, first the
Cumulative Fraction Released (CFR) is given by the following equation:

Drugreleased at any time, t−Initial Amount Q t −Q 0

CFR= = (
Total amount of drug present QT
SEQ Equation¿ ARABIC37)

Dividing equation (36) by QT, the total amount of the drug released/present gives:

K0
CFR= t ( SEQ Equation¿ ARABIC38)
QT

Recalling the assumption that Q0 is very small, and can be assumed to be 0. Introducing a
constant k0:
 K0
k 0= ( SEQ Equation¿ ARABIC39)
QT

CFR=k 0 t (SEQ Equation¿ ARABIC40)

The plot of CFR vs. time should give a straight line with a slope of k0 passing through the origin.

Hixson-Crowell. In this model, the following assumptions are made:

 Dissolution occurs normal to the surface of the solute particles.
 Agitation is uniform over the exposed surface.
 The particles are spherical.

Using a special form of Fick’s law known as the Noyes-Whitney equation to describe the
dissolution of the drug,

dW kA (C s−C ∞ ) ( SEQ Equation¿ ARABIC66 )

=
dT l
Where dW/dT represents the rate of dissolution, k is the Noyes-Whitney constant and
contains the diffusion constant D, A is the surface area, Cs is the solute concentration, Co is the
concentration of the bulk solution, which in this case is assumed to be zero, and L is the diffusion
layer.

Simplifying the previous equation gives:

(C s) ( SEQ Equation¿ ARABIC67 )

dW =kA dt
l
The mass is represented as follows and is taken as negative because we are dealing with drug
loss,

dW =−ρdV (SEQ Equation¿ ARABIC68)

Since liposomes are considered to be spherical in shape (N represents the number of spheres),

4
V = π r3 N ( SEQ Equation ¿ ARABIC69)
3
dV
=4 πN r 2 ( SEQ Equation ¿ ARABIC70)
dr
Next, combining equations 67 and equations 68 and substituting for dV and A, we get the
following:

k 4 πN r 2 C s dt
dW =−ρ 4 πN r dr=
2
(
l
SEQ Equation¿ ARABIC71 )

Eliminating similar terms and integrating on both sides,

rt
k Cs t
∫− ρdr= dt ( SEQ Equation¿ ARABIC72)
ro
l ∫0

k CS T
−( r −r o ) = ( SEQ Equation¿ ARABIC73)
ρl
−k C S T
rt = + ro ( SEQ Equation¿ ARABIC74 )
ρl
Given that we require the results in terms of CFR, the weight of dissolution W is used
instead of the volume. Therefore, for N spheres the volume is:

4
V = π r 3 N (69)
3

The weight of each sphere can be expressed as:

4 3
W =ρ πr N ( SEQ Equation¿ ARABIC75)
3
Raising all variables to the cubic root and re-arranging for r yields:

1
3
W
r= 1 ( SEQ Equation¿ ARABIC76)
4
( ρ πN
3 ) 3

Equating equation 73 and equation 74 while also expressing ro in the form provided by equation
76 gives:
 1 1
3 3
Wt −k C S T Wo
1
= + 1 (
4 4 ρl
( 3
ρ
πN ) ρ πN
3
3 ( ) 3

SEQ Equation¿ ARABIC77)

Simplifying the above equation into the Hixson-Crowell form,

1 1 1
−k C S T 4
Wt = 3
ρl
ρ πN +W o 3
3
3
( ) ( SEQ Equation ¿ ARABIC78)

Let K’ represent the constant related to the surface, the shape and the density of the particle,

1 1
k K ' CS T 1
W 0 3 −W t 3 = ( N )3 ( SEQ Equation¿ ARABIC79)
l
Re-defining the model in terms of CFR to make compatible with the variables used in this
research,

Drugreleased at any time, t−Initial Amount C t−C 0 W t−W 0

CFR= = = (
Total amount of drug present CT W0
SEQ Equation¿ ARABIC80)

Simplifying and linearizing the above equation yields:

1
[ ( 1−CFR ) ]3 =K HC t ( SEQ Equation¿ ARABIC81)

Here KHC represents the release constant and according to equation 81 a plot of [(1-
CFR)]1/3 versus time would yield a straight line with a slope of KHC.

5.6.5. Korsmeyer-Peppas (Power Law) Model. The Korsmeyer-Peppas model has the
simple form:
CFR ≈ k kp t n ( SEQ Equation¿ ARABIC82)

Where kkp is a constant that accounts for the structural and geometrical characteristics of
the DDS, and n is the release exponent which characterizes the drug release mechanism. Starting
with Fick’s second law in three-dimensional space,
∂C ∂2 C ∂2 C ∂2 C
∂t
=D ( + +
∂ x2 ∂ y2 ∂ z2 ) (

SEQ Equation¿ ARABIC83)

Here C represents concentration, D is the diffusion coefficient and x, y and z represent the
direction of diffusion.

Assuming diffusion of the drug only in the x-direction the expression reduces to:

∂C ∂2 C
=D 2 ( SEQ Equation¿ ARABIC84 )
∂t ∂x
This second order differential equation can be solved using the error function, and
numerical methods, an approach that was initially described and derived by John Crank in 1975
[118]. The general solution for the above differential equation for a non-steady state general
boundary conditions problem where the surface concentrations are constant and the initial
distribution within the DDS is given by a function of position f(x) can be expressed by the
following trigonometric series:

t ≥ 0 , x=0 , C=C1

t ≥ 0 , x=l ,C=C 2

t=0 , 0< x <l ,C=f (x )

2 2 2 2
∞ − Dn π t ∞ −D n π t 1
x 2 C2 cos ( nπ )−C1 nπx 2 nπx nπ x'
C=C 1+ ( C2−C 1 ) + ∑
l π 1 n
sin
l
e
2
l
+ ∑ sin
l 1 ( )
π
e l
2

∫ f ( x ' ) sin
0
( )
l
d x'

(SEQ Equation¿ ARABIC85)

Assuming uniform initial distribution and equal surface concentrations, the boundary conditions
are:

l l
t=0 ,− < x < ,C=C 0
2 2

l
t >0 , x =± , C=C 1
2
 The physical meaning of these conditions is that initially, within the drug carrier, the
concentration is uniformly the initial concentration of the drug, C0. Then at any time, t, the
concentration of the drug at the boundary between the DDS and the solution is equal and
constant at C1. These conditions may be interpreted as perfect sink conditions, where the drug
has an endless sink to dissolve into, and the DDS is separated from the solution by a membrane.
Now, the earlier solution can be simplified to be:
2
∞ − D ( 2 n+1 ) π2 t
C−C 0
C1−C 0
4
=1− ∑
8
π n=0 ( 2 n+ 1 )2 π 2
e 4l
2

cos ( (2 n+12l ) πx ) ( SEQ Equation ¿ ARABIC86 )

By rearranging and integrating the equation to yield Mt the total amount of the drug diffused into
the solution, and M ͚ the total amount of the drug diffused after infinite time,
2
∞ − D ( 2 n+1 ) π2 t
Mt 8 2

=1−∑ 2 2
e 4l
( SEQ Equation¿ ARABIC87 )
M∞ n=0 ( 2 n+1 ) π

Using the error function to derive a more simplified form of the above equation that is useful for
small intervals of time,

Mt Dt 1

M∞
=2 2
l ( )¿ 2
( SEQ Equation¿ ARABIC88 )

Where,

∞
2 2

( SEQ Equation¿ ARABIC89)

erfc ( z )=1−erf ( z )= ∫ e−t dt
√π z
And subsequently,

∞
1 2

ierfc ( x ) =∫ erfc ( z ) dz = 1
e− x −x erfc ( x ) ( SEQ Equation¿ ARABIC90 )
x 2
π
In the above equation as the argument of the ierfc function increases toward infinity, its
value decreases to a value close to 0. Thus, the smaller the time intervals the argument for the ierfc
function becomes infinitely large, yielding a small contribution from the ierfc term. Consequently,
the second term from the derived equation tends to 0 and can be removed from the expression
when dealing with small intervals of time, giving:
Mt Dt 1

M∞
=2
( )
π l2
2
( SEQ Equation¿ ARABIC91)

Taking the Korsmeyer-Peppas constant as:

1
D
k kp=2 ( )
π l2
2
( SEQ Equation ¿ ARABIC92)

Again to express the equation in terms of the variables used in this research the value for

Mt
is taken to be equal to CFR (assuming the initial amount of the diffused drug is minute
M∞
enough to assume it to be 0), and introducing the constant from equation 92, then the above
relation can be denoted as:

1
Mt
CFR= =k t 2 ( SEQ Equation¿ ARABIC93 )
M ∞ kp

The above expression is similar to the Korsmeyer-Peppas model introduced at the

beginning of the section. Thus, if CFR is plotted against the square root of time, a straight-line
graph will be observed, with a slope of 2(D/πl2)1/2. This is the case where Fick’s Law holds true.
In most cases, the release mechanism deviates from Fick’s Law, as there is usually more than
one release mechanism in use. This leads to a more generic equation that explains a range of
release mechanisms:

Mt
CFR= =a t n ( SEQ Equation¿ ARABIC94 )
M∞

As mentioned earlier, n characterizes the different release mechanisms. Taking the logarithms of
both sides of the equation,

log ( CFR )=log ( a )+ nlog ( t ) (SEQ Equation¿ ARABIC95)

Thus, if log(CFR) is plotted against the logarithm of time, a straight-line graph can be obtained
with a y-intercept at log(a), where a, in this case, is kkp, and the slope is n.
 Baker-Lonsdale Model. The Baker-Lonsdale model is a modification of the Higuchi
model used to describe drug release from spherical matrices and is based on the assumption that
the matrix is homogenous and has no fractures that will cause unintended release.
Mathematically the model is represented by:
2
M M t 3 Dm C ms
3
2 [ ( )]
1− 1− t
M∞
3
−¿
M∞
= 2
r0 C 0
t ( SEQ Equation¿ ARABIC106

Where M t is the amount of drug released at time t, M ∞ is the amount of drug released at
infinite time, Dm is the diffusion coefficient, C ms is the drug solubility in the matrix, r 0 is the of
the spherical matrix and C 0 is the initial concentration of the drug in the matrix. Assuming that
the initial release of the drug is negligible and re-defining the equation in terms of CFR:

Mt
=CFR ( SEQ Equation ¿ ARABIC107 )
M∞

Equation 106 becomes:

2
3
2
[ ]
1−( 1−CFR ) 3 −¿ CFR=k BL t ( SEQ Equation¿ ARABIC108

)
Where;

3 Dm Cms
k BL= ( SEQ Equation¿ ARABIC109)
r 20 C0
2
[ ]
Thus, if 3 1−( 1−CFR ) 3 −¿ CFR was plotted against time, t, a straight line with slope k BL can
2
be obtained.